Our laboratory has a longstanding interest in the molecular pathogenesis of aplastic anemia and other forms of bone marrow failure (BMF). In children about 25% of cases of BMF are inherited, while in adults the percentage is even lower; most cases of BMF in children and adults are classified as idiopathic. Patients with inherited forms of BMF have a predisposition to develop myelodysplastic syndrome (MDS), leukemia, squamous cell carcinoma, and other forms of cancer. Our laboratory was involved in the recent discovery that individuals with autosomal dominant dyskeratosis congenita (DKC), an inherited form of BMF associated with cancer susceptibility, have mutations in the gene encoding the telomerase RNA subunit (hTERC). Clinical signs in patients with autosomal dominant DKC are often mild and are easily missed. Based on this observation we postulate that mutations in hTERC may be responsible for a significant number of cases of BMF, including cases currently classified as idiopathic. Moreover, because bone marrow cells from patients with various forms of BMF have been observed to have relatively short telomeres, we hypothesize that excessive telomere shortening in hematopoietic stem cells may play a central role in the pathogenesis of BMF and cause increased genomic instability that predisposes to the development of cancer. To test these hypotheses, an unselected cohort of children and adults diagnosed or treated for BMF at Washington University or at identified collaborating institutions will be invited to participate in the proposed study. Similarly, a selected patient cohort will be enrolled from the International Aplastic Anemia and Myelodysplasia Society and other international bone marrow failure registries. After obtaining informed consent, DNA isolated from peripheral blood cells or from a skin biopsy will be examined for mutations in the hTERC gene and for telomere length/integrity studies. Detailed clinical and family history information will be obtained for each participant using standardized forms and procedures. There are several goals of this study: 1) to determine the frequency of hTERC gene mutations; 2) to delineate the heritability, penetrance and expressivity of hTERC gene mutations; and 3) to investigate whether the onset and severity of BMF correlates with telomere length and integrity. The proposed studies will help to elucidate the clinical consequences of mutations in the hTERC gene and provide new revolutionary insights into the pathogenesis of BMF. The results may indicate genetic analysis of the hTERC gene should become a routine prognostic test for all patients diagnosed with BMF. The characterization of the clinical consequences of hTERC gene mutations is likely to have a direct impact on the clinical management of patients with BMF due to hTERC gene mutations and their family members. The proposed studies will also increase the knowledge of the role of dysfunctional telomeres in human disease, including the molecular genetic pathways in tumor initiation and progression, their role in degenerative diseases, and in aging. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]